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Principal Investigator: Roland Horst Friedel
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $421,025
Funding agency: National Institute of Neurological Disorders and Stroke
The malignant brain tumor glioblastoma (GBM) is highly infiltrative. Migrating GBM cells are exposed to
biomechanical forces during tumor invasion, however, little is understood of the mechanosensitive pathways
that enable GBM cells to gain invasiveness. Here, we postulate that Plexin guidance receptors, focusing in this
proposal on Plexin-B2 and its paralog Plexin-D1 (both highly upregulated in GBM and correlated with poor
patient survival), may function as key mechanoregulators to enhance mechanotension-induced glioma cell
migration. Our hypothesis is built upon a series of exciting recent discoveries: in orthotopic transplant models,
using patient-derived GBM stem cells (GSCs), we found that Plexin-B2 knockout (KO) resulted not only in
reduced tumor spread, but also strikingly a change of migration preference from axon tracts to peri-vascular
routes. Moreover, while GSCs spread on both soft and stiff substrates in stripe assays, Plexin-B2 KO GSCs
congregated on stiff stripes, a migratory behavior known as durotaxis. The ability of Plexin-B2 to empower
GBM cells to overcome durotaxis tendency has clinical significance: as GBM progresses, the bulk of the tumor
gradually stiffens, in part from increased pressure; tumor cells therefore must find a way to break from tumor
bulk to invade softer brain parenchyma, and our preliminary data suggest that Plexin upregulation might fulfill
this role. To further dissect mechanotension-induced GBM invasion, we will study mechanistic details of Plexin-
B2 and -D1 as mechanoregulators in governing GBM invasion, with the aim to identify novel targets to curb
GBM infiltration. In Aim 1, we will expand in vivo transplant studies to test how Plexin-mediated GBM invasion
patterns and migratory paths applies to different GBM subtypes. We will then investigate how differentiation
status and metabolic niche (hypoxia) may alter the choice of migration routes in dependence of Plexins. We
will validate these findings in human GBM tissues. In Aim 2, we will delve into how Plexins operate to promote
invasiveness. We will apply a series of mechanosensitive assays to interrogate Plexin-mediated biomechanical
properties of migrating GBM cells, including intercellular adhesiveness, cell dispersion capacity, actomyosin
dynamics, as well as infiltrative behavior in 3D vascular models. We will test how migrating GBM cells respond
to different substrate stiffness, matrix substrates, and dissociated state, and how Plexins may alter durotactic
behavior. We will define mechanoresponse pathways in GBM cells and use them as readouts to directly test
Semaphorin- and mechano-dependent functions of Plexins. Finally, in Aim 3, we will interrogate downstream
effectors of Plexin-B2 mechanosignaling. This includes the interaction of Plexins with the mechanosensitive
Hippo/YAP pathway, and potential relay mechanisms through intracellular proteins Rap2 or AMOT. In sum, by
studying mechano-sensitive mechanisms of GBM invasion, we explore new paradigms of GBM malignancy,
with the ultimate goal to identify new therapeutic opportunities against this lethal cancer.
Terms: <3-D><3-D modeling><3-Dimensional><3D><3D modeling><AMOT><AMOT gene><Actomyosin><Adhesiveness><Angiomotin><Assay><Attenuated><Axon><Behavior><Binding><Bioassay><Biochemical><Biological Assay><Biomechanics><Blood Serum><Blood Vessels><Body Tissues><Brain><Brain Cancer><Brain Nervous System><Cancers><Cell Body><Cell Communication and Signaling><Cell Line><Cell Locomotion><Cell Membrane Lipid Rafts><Cell Migration><Cell Movement><Cell Signaling><CellLine><Cells><Cellular Migration><Cellular Motility><Characteristics><Data><Dependence><Development><Diffuse><Dissociation><Elements><Encephalon><Environment><Exposure to><Face><Future><Genes><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Grant><Human><Hypoxia><Hypoxic><Infiltration><Infiltrative Growth><Intracellular Communication and Signaling><Invaded><Knock-out><Knockout><Light><Link><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mechanics><Mediating><Mediation><Mediator><Membrane><Membrane Microdomains><Metabolic><Modeling><Modern Man><Molecular><Molecular Interaction><Monomeric G-Proteins><Monomeric GTP-Binding Proteins><Negotiating><Negotiation><Neuroglial Neoplasm><Neuroglial Tumor><Oxygen Deficiency><Pathway interactions><Patients><Pattern><Photoradiation><Progenitor Cell Transplantation><Progenitor Cells><Property><Proteins><Receptor Protein><Regulation><Role><Route><Semaphorins><Series><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Small G-Proteins><Small GTPases><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Stem Cell Transplantation><Stem cell transplant><Strains Cell Lines><Stress><Surface><Testing><Tissues><Traction><Transducers><Transplantation><Tumor Cell><Tumor Cell Invasion><Tumor Invasion><Up-Regulation><Upregulation><Xenopus B2 antigen><attenuate><attenuates><axon growth cone guidance><axon guidance><biological signal transduction><biomechanical><brain parenchyma><brain tissue><cell motility><cell type><clinical significance><clinically significant><cultured cell line><design><designing><developmental><empowerment><experiment><experimental research><experimental study><experiments><faces><facial><gain of function><gene signatures><genetic signature><glial-derived tumor><glioblastoma multiforme><in vivo><interstitial><lipid raft><live cell image><live cell imaging><live cellular image><live cellular imaging><loss of function><malignancy><mechanic><mechanical><membrane structure><migration><mutant><neoplasm/cancer><neoplastic cell><neural><neuroglia neoplasm><neuroglia tumor><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><paralog><paralogous gene><pathway><plexin><preference><pressure><progenitor transplantation><receptor><social role><spongioblastoma multiforme><stem and progenitor cell transplantations><stem cells><three dimensional><three-dimensional modeling><translational study><transplant><transplant model><tumor><validation studies><vascular>